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Between them, gallstones and alcohol cause over 80% of all cases of acute pancreatitis. Although most cases of gallstone pancreatitis are mild, 10-15% are severe, requiring prolonged hospitalization and skilled medical care. Some of these patients die from local and systemic complications of their pancreatitis, which is a complex disorder requiring considerable experience and expertise to manage. Predictive scoring systems, derived from historical data, allow clinicians to identify those who are likely to develop severe disease. Severe acute pancreatitis is a condition that becomes progressively worse over time due to local, then systemic, effects of inflammatory mediators such as cytokines. Research efforts are currently focused on developing drugs that will block or ameliorate their effects. The platelet activating factor (PAF) inhibitor, lexipafant, is showing promise in clinical trials. With the possible exception of gabexate, a protease inhibitor, no other drug or medical intervention has been shown to alter the course of pancreatitis once it is established. The care of patients with severe pancreatitis includes vigorous fluid resuscitation, generous analgesia, enteral or parenteral nutrition when ileus is prolonged, and management of complications as they arise. In cases of gallstone pancreatitis, therapeutic endoscopy has a role when gallstones are impacted in the ampulla of Vater. Four clinical trials have compared early ERCP and sphincterotomy for biliary stone extraction to medical management alone. In patients with biliary obstruction (progressive jaundice with or without cholangitis), early ERCP reduces morbidity related to biliary sepsis. There is also a trend towards fewer deaths. However, there appears to be no benefit from early ERCP in patients with severe pancreatitis who do not have biliary obstruction. A recent study suggests that unnecessary ERCP in this setting may actually increase complications, such as respiratory and renal failure.